This invention relates a method of administering the dihydrotestosterone precursor hormone 5alpha-androstanediol or 5alpha-androstanedione as a means of increasing dihydrotestosterone levels in humans. Although testosterone is considered to be the primary male androgen, in many sites of action it is actually dihydrotestosterone that is the active form of this steroid. Dihydrotestosterone (DHT) is a more potent form of testosterone, shown to be roughly three to four times more active in the human body in comparison. Its higher level of activity is attributed to the ability of this hormone to bind to the androgen receptor with greater affinity, and with more stability, than testosterone. The activity of DHT is most closely related to the development and maintenance of male sexual characteristics, including external virilization, sexual maturity at puberty, spermatogenesis, sexual behavior/libido and erectile functioning. DHT has also been shown to be equally effective as testosterone at inducing the expected benefits of androgen replacement on mood, sexual function, bone and muscle.
A number of methods have been developed to restore androgen concentration in humans with declining levels. Several injectable esterified testosterone preparations have been fashioned that allow a slow release of hormone into the blood stream over the course of several days to weeks for example, however all provide inconsistent dosing as there is great variance in hormone release from the site of injection, such that a short supraphysiological rush may eventually be followed by days of subnormal hormone concentrations. The buildup of estrogens due to the natural process of aromatization may exaggerate the side effects to such medication, particularly at times when testosterone levels are abnormally high, as supraphysiological levels of estrogens in the male body have been linked to gynecomastia (female breast tissue development), water retention and edema, and increased fat deposition. More basically, recent studies have made clear that both androgens and estrogens play a synergistic role in the promotion of benign prostatic hypertrophy (BPH). This suggests that an aromatizable androgen such as testosterone may be less than ideal for use in older men at risk for such disease.
Also a number of synthetic oral androgen derivatives have been developed including methyltestosterone, fluoxymesterone and stanozolol. All such compounds are alkylated at the 17.sup.th carbon position (alpha orientation), an alteration that inhibits reduction of the steroid to inactive 17-ketosteroid form. While this greatly improves oral bioavailability of the compound, this alteration has also been shown to place stress on the liver, in some instances resulting in organ damage. Although the use of a c-17 alpha alkylated oral androgen may prove much more comfortable for the patient in terms of dosing and control over blood hormone level compared to an injectable preparation, the possible risk of developing complications with liver functions may make them much less useful for androgen replacement compared to injectable preparations, particularly for extended periods of therapy.
In searching for a less toxic, more reliable oral alternative for androgen replacement the use of androgen precursor hormones have been suggested. U.S. Pat. No. 5,578,588 to Mattern et al. relates a method of using a precursor hormone, namely androstenedione, as a means of increasing testosterone levels. The pharmacokinetics of administering such a precursor are such that hormone concentrations of active hormone (testosterone) peak within 90 minutes, and subsequently decline over a period of three to four hours. This more closely resembles the natural pulsating pattern in which the body releases testosterone, and avoids the prolonged peaks and troughs noted with use of esterified injectable hormone preparations. Although the precursor hormone androstenedione discussed in this patent has been shown to effectively convert to testosterone after administration, it is also open to alteration by the aromatase enzyme. Its use may therefore result in an undesirable buildup of serum estrogen levels. This has been made clear in a recent study by Douglas King et al. (JAMA June; 1999 281(22):2020-28), which demonstrated that the rise in estrone and estradiol levels after administration of androstenedione was much more pronounced, and possibly more important physiologically, than that of testosterone.
U.S. Pat. No. 5,880,117 to Patrick Arnold. relates a method of using the precursor hormone 4-androstenediol as a means of increasing testosterone levels in humans. This hormone represents an improvement over androstenedione, as 4-androstenediol does not seem to be open to aromatase in its initial state. The possibility that this compound will preferentially convert to an estrogen over an androgen is likewise nonexistent. This compound also seems to convert to testosterone with greater efficacy than androstenedione, representing a second improvement of note in this invention. The end product testosterone however is still readily aromatized. So while the compound suggested in this patent does offer advantage over a previous patent in that the compound in question avoids a direct path of estrogen conversion and is more actively transformed to active state, the target hormone of replacement may still be less than ideal in many circumstances.